Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Although the prognosis is relatively good, survival of patients is reduced despite surgical removal of the tumor and radioactive iodine treatment. About 40% of adult and 80% of childhood patients have regional lymphatic metastasis at the time of diagnosis. Regional lymphatic metastasis does not reduce survival, but is associated with recurrence of PTC. This feature suggests that anti-cancer factors secreted from immune cells in the lymph nodes may reduce the progression of PTC. In those whose tumor progresses beyond the regional lymph nodes, resistance to the anti-cancer factors may have developed. The long-term goal of the proposed research is to characterize the mechanisms by which the cytokine, tumor necrosis factor-alpha (TNF), contributes to controlling the progression of human papillary thyroid carcinoma. In addition, the mechanism by which PTC cells develop resistance to TNF will be characterized. Further, the relationships between TNF receptor subtype expression and the mechanisms of TNF-induced antiproliferation and TNF resistance will be determined. The molecular mechanism of TNF action involves activation of transcription factors, such as nuclear factor kappa B (NF-kappaB) and Jun-B/AP-1 (Jun-B homodimer and Jun-B-c-Fos heterodimer form of activator protein-1), and translation factors, such as eukaryotic initiation factor 4E, that coordinate the expression of genes regulated by TNF. The working hypotheses are: 1) that TNF controls PTC progression through activation of NF-kappaB and 2) that PTC cell resistance to TNF is mediated by activation of Jun-B/AP-1, resulting in further progression of PTC. The specific aims of the proposed research are: 1. To elucidate the molecular mechanism of the antiproliferative action TNF on human papillary thyroid carcinoma cells. 2. To elucidate the mechanism by which TNF resistance develops in resistant human papillary thyroid carcinoma cells.